This is a study to investigate the potential clinical benefit of G1T48 as an oral selective estrogen receptor degrader (SERD) alone and in combination with palbociclib, a cyclin dependent kinase 4/6 (CDK 4/6) inhibitor, in patients with estrogen receptor-positive, HER2-negative metastatic breast cancer.

The study is an open-label design, consisting of 3 parts: dose-finding portion including food effect (Part 1), G1T48 monotherapy expansion portion (Part 2), and G1T48 in combination with palbociclib expansion portion (Part 3). All parts include 3 study phases: Screening Phase, Treatment Phase, and Survival Follow-up Phase. The Treatment Phase begins on the day of first dose with study treatment and completes at the Post-Treatment Visit. Approximately, 184 patients may be enrolled in the study.

Inclusion Criteria:

• For Part 1, postmenopausal women only

• For Parts 2 and 3, any menopausal status

• Confirmed diagnosis of ER-positive, HER2-negative advanced breast cancer, not amenable to curative therapy

• For Part 1, prior treatment with less than 4 prior lines of chemotherapy

• For Part 2, prior treatment with less than 2 prior line of chemotherapy

• For Part 3, prior treatment with no more than 1 prior line of chemotherapy

• For Parts 1 and 2, prior treatment with less than 4 prior endocrine therapies for metastatic breast cancer

• For Part 3, prior treatment with no more than 1 prior line of endocrine therapies for metastatic breast cancer

• For Parts 1 and 2, patients must satisfy 1 of the following criteria for prior therapy:

  • Progressed during treatment or within 12 months of completion of adjuvant therapy with an aromatase inhibitor
  • Progressed after the end of prior aromatase inhibitor therapy for advanced/metastatic breast cancer

• For Part 3, patients must satisfy 1 of the following criteria for prior therapy:

  • Received ≥ 24 months of endocrine therapy in the adjuvant setting prior to recurrence or progression
  • Received ≥ 6 months of endocrine therapy in the advanced/metastatic setting prior to progression

• For Part 1, evaluable or measurable disease

• For Parts 2 and 3, evaluable (approximately 25%) or measurable disease (approximately 75%) as defined by RECIST, Version 1.1 including bone-only disease

• ECOG performance status 0 to 1

• Adequate organ function

Exclusion Criteria:

• For Part 3, prior treatment with CDK4/6 inhibitor, investigational oral SERDs or SERCAs in any setting
• Active uncontrolled/symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease
• Anticancer therapy within 14 days of first G1T48 dose or within 28 days for antibody-based therapy
• Concurrent radiotherapy, radiotherapy within 14 days of first G1T48 dose, previous radiotherapy to the target lesion sites, or prior radiotherapy to > 25% of bone marrow
• Prior hematopoietic stem cell or bone marrow transplantation